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Therapeutic interventions targeting enteropathy in severe acute malnutrition modulate systemic and vascular
Jonathan P Sturgeon1, Kuda Mutasa2, Mutsa Bwakura-Dangarembizi3
1Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe; Blizard Institute, Queen Mary University of London, London, UK.
Insights
Novel interventions for severe acute malnutrition (SAM) in children showed promising biomarker results. Treatments targeting enteropathy reduced inflammation and improved gut barrier function, supporting further clinical trials.
Area of Science:
- Pediatric Nutrition
- Gastroenterology
- Immunology
Background:
- Severe acute malnutrition (SAM) is a life-threatening condition in children, associated with high mortality.
- Complicated SAM involves multisystem dysfunction, including inflammation and gut enteropathy.
- Novel interventions are needed to address the underlying pathology of complicated SAM.
Purpose of the Study:
- To analyze tertiary outcomes of interventions for malnutrition enteropathy in children with SAM.
- To evaluate the effects of budesonide, N-acetylglucosamine, colostrum, and teduglutide on biomarkers.
- To explore the relationship between systemic inflammation and enteropathy markers.
Main Methods:
- Analysis of a phase II multi-center trial in Zambia and Zimbabwe.
- 122 children with SAM received one of four interventions or standard-of-care for 14 days.
- Multiplex biomarker analysis of plasma samples using Luminex and ELISA, followed by principal component analysis.
Main Results:
- Budesonide and colostrum reduced systemic inflammation markers.
- Colostrum improved epithelial barrier function markers (GLP2, angiopoietin) and reduced lipopolysaccharide.
- N-acetylglucosamine increased epithelial regeneration and growth factor biomarkers.
Conclusions:
- Interventions for malnutrition enteropathy demonstrated plausible effects on inflammation and regeneration biomarkers.
- An interdependence between systemic inflammation and enteropathy markers was observed.
- These findings support larger trials to assess clinical benefits in children with complicated SAM.
Background:
Severe acute malnutrition (SAM) is the most life-threatening form of undernutrition, and children hospitalised with complications have unacceptably high mortality. Complicated SAM is a multisystem disease characterised pathophysiologically by muscle wasting, systemic inflammation, metabolic dysfunction, and malnutrition enteropathy including epithelial barrier dysfunction. There is a clear need for novel interventions to address the underlying pathogenic perturbations of complicated SAM.
Methods:
In this analysis of tertiary outcomes from a phase II multi-centre trial in Zambia and Zimbabwe, multiplex biomarkers were measured in 122 children (57% male) with SAM randomised following stabilisation ('baseline') to one of four interventions for 14 days to treat malnutrition enteropathy: budesonide, N-acetylglucosamine, colostrum, or teduglutide, compared with standard-of-care. Following measurement of 35 biomarkers from day 15 plasma samples using Luminex and ELISA, the dimensionality of biomarker data was reduced using principal component analysis.
Findings:
Both budesonide and colostrum reduced systemic inflammation (as measured by CD14, IL1-ra, CRP, and LBP), while children receiving colostrum had higher GLP2 and angiopoietin, and lower circulating lipopolysaccharide, suggesting better restoration of epithelial barrier function. N-acetylglucosamine, a precursor for epithelial glycosaminoglycan synthesis, increased biomarkers of epithelial regeneration (EGF, VEGF), and circulating growth factors (angiopoietin, IGFBP-3, and GCSF).
Interpretation:
Interventions aimed at ameliorating malnutrition enteropathy showed plausible effects on biomarkers of inflammation and epithelial regeneration, demonstrating an interdependence of systemic inflammation and enteropathy markers seen in structural analysis. Given the interplay between inflammation and tissue restoration in malnutrition, this mechanism of action supports larger trials to determine the clinical benefits of interventions, either alone or in combination, in children with complicated SAM.
Funding:
This analysis of tertiary outcomes for the TAME trial was funded by a Wellcome grant to JPS (220566/Z/20/Z). The TAME trial was funded by a grant from the Medical Research Council (UK), number MR/P024033/1. AJP is funded by Wellcome (108065/Z/15/Z). Takeda UK provided teduglutide at a discounted price.
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